The discovery of endothelial progenitor cells (EPCs) by Asahara et al in 1997 has provided an insight into the pathogenesis of many vascular disease states such as ischaemia, restenosis and pulmonary hypertension1-6. Urbich et al have recently defined EPCs as highly proliferative non-endothelial cells which arc capable of transdifferentiating into endothelial cells7. EPCs can be isolated from various sources, including bone marrow, peripheral blood and umbilical cord blood8-10. There are two phenotypes of EPCs (early versus late EPCs) which both have distinct proliferative and angiogenic potential8,11. The ability to adhere to matrix molecules such as fibronectin, incorporate acLDL and bind lectin remains the commonly used definition for EPCs, but, increasingly, further flow cytometry analysis and immunostaining with various markers such as haematopoeitic markers and endothelial markers are utilised to define EPCs12-15.
Patients with type 116 and type 217,18 diabetes mellitus have a lower number of EPCs as compared to healthy volunteers. Patients with type 2 diabetes complicated with peripheral vascular disease have even lower number of EPCs compared to those without complications18. EPC number in these patients inversely correlates with glycaemic control16-18. EPCs isolated from patients with type 2 diabetes had decreased adhesion to activated endothelial cells, and to matrix molecules such as collagen and fibronectin17. EPCs derived from patients with both types of diabetes have impaired ability to form tubules in vitro16,17. Furthermore, bone marrow mononuclear cells derived from streptozotocin induced diabetic mouse differentiate less efficiently into EPCs in vitro and are less likely to form tubules than those derived from non-diabetic mice19. The conditioned media from EPCs isolated from patient with type 1 diabetes has a reduced angiogenic capacity and may contain inhibitors of tubule formation in vitro16. The phenotype of EPCs derived from patients with type 1 diabetes also remains unchanged even after culture in normoglycaemic conditions16.
Osteopontin (OPN) is an arginine-glycine-aspartic acid (RGD)-containing glycoprotein. It is involved in cell migration, cell survival, regulation of immune cell function, inhibition of calcification and control of tumor cell phenotype23-25. Osteopontin enhances tumour growth26, and its progression27. In the setting of primary non-small cell lung cancer, overexpression of OPN increases the aggressiveness of the tumour28. Inhibition of OPN expression by either an inducible short-hairpin RNA vector29, RNA interference30 or antisense oligonucleotides31 attenuates the aggressiveness of various tumours.
The prevalence and fatality of cardiovascular disease (CVD) worldwide is testament to the inefficiency of current therapeutic regimes. A fundamental element in many cardiovascular diseases is the loss of functional cardiomyocytcs. Apoptosis is associated with many cardiovascular conditions, such as myocardial infarction and heart failure, however the precise mechanisms are unknown. We have identified OPN as a therapeutic target in the prevention of cardiomyocyte death and CVD. Management of expression of candidate genes in patients with cardiovascular disease may greatly enhance their life expectancy. More importantly, regulation of expression of these genes in individuals predisposed to CVD may prevent the onset of the disease. In myocardial complications apoptosis has been observed repeatedly in compromised human hearts and has been proven to be a major contributor to cardiomyocyte death during ischemic/reperfusion (VR) injury and cardiomyopathy (Gottlieb R A, The Journal of Clinical Investigation 1994, Fliss H, Circulation Research 1996).